DESCRIPTION (provided by investigator): NTDs are a group of common, structural malformation that is associated with excess morbidity and mortality. A specific etiologic agent(s) cannot be identified in the majority of individuals with NTDs, and in this group of patients the condition is believed to be a genetically complex trait. Both maternal diabetes and pre-pregnancy obesity have long been identified as significant independent risk factors for NTDs. Evidence accumulated to date suggests that the excess of NTDs among infants born to obese and to diabetic mothers may share some common underlying mechanisms. Child-bearing age women who are genetically susceptible to diabetes/obesity may have altered glucose homeostasis, even if they are non-diabetic;therefore, producing a highly compromised in utero environment and exposing the developing embryos to teratogenic molecules (e.g., extra glucose flux). Genetic factors predisposing the developing embryos themselves to diabetes/obesity-related teratogenicity may modify any given infants'risk of having an NTD. In this application, we propose to investigate the genetic susceptibility to the induction of NTDs as a result of altered maternal glucose homeostasis, energy metabolism and embryonic glucose transport related mechanisms. A comprehensive evaluation of the association between variants in the candidate genes and NTDs will be undertaken using data from a large collection of NTDs case-parent triads (N=850) from the National Birth Defects Prevention Study. Findings that implicate one or more of these genes as maternal or embryonic risk factors for NTDs will guide future research efforts, by identifying new genes and/or genetic pathways that may influence neural tube development. Negative findings, although less exciting, will also help to guide future research efforts by narrowing the list of candidate genes for inclusion in subsequent studies. Clinically, positive findings could lead to improved risk assessment strategies and genetic counseling for families affected by NTDs. PUBLIC HEALTH RELEVANCE: Neural tube defects are common, serious birth defects that affect approximately 324,000 births worldwide and 3,000 pregnancies in the United States annually. Diabetes and obesity are significant public health issues as well as risk factors for NTDs. Our proposed studies will investigate the association between candidate genes among maternal diabetes/obesity-related pathways and NTD risk. These studies will help to establish or refute these genes as NTDs risk factors. This information will be used to guide future studies and could lead to novel prevention strategies, improved risk assessments and genetic counseling for individuals and families affected by NTDs.